1. Field of Invention
The present invention relates to a novel process for preparation of 3-pyrrolidinols, optionally substituted in the 1, 2, 3 and 4 positions and to certain novel 4-amino-3-hydroxybutyronitrile chemical intermediates therefor. The process involves reductive cyclization of 4-amino-3-hydroxybutyronitriles, Raney nickel being the required catalyst.
2. Information Disclosure Statement
Heretofore, several routes to pyrrolidinols have been available for use as described in U.S. Pat. Nos. 2,838,521 and 2,882,276 and in SYNTHETIC COMMUNICATIONS 13 (13) 1117-1123 (1983).
These methods include:
(1) Commercial conversion of 1, 2, 4-butanetriol to 1,4-dibromo-2-butanol with hydrogen bromide at 140.degree. C. followed by condensation with a secondary amine. Debenzylation of N-benzyl-3-pyrrolidinol so produced with hydrogen over palladium on carbon leads to 3-pyrrolidinol; PA0 (2) Reduction of N-substituted-3-pyrrolidinones with lithium aluminum hydride; PA0 (3) Heating cis 1,4-dichloro-2-butenes with benzylamine to produce N-benzyl-3-pyrrolidinol and debenzylating as in (1) above; and PA0 (4) Heating malic acid with benzylamine in ethanol at 170.degree. C. to give N-benzyl-3-hydroxysuccinimide and reducing with lithium aluminum hydride to give N-benzyl-3-pyrrolidinol. PA0 t-butoxycarbonyl (deprotect with acid), PA0 isobutyloxycarbonyl (deprotect with ammonia and pyridine), PA0 .beta., .beta., .beta.-trichloroethoxycarbonyl (deprotect with zinc and acetic acid), or PA0 benzyloxycarbonyl (deprotect with strong acid, e.g., HCl, HBr, HI or hydrogenation); PA0 phenylmethyl (deprotect by hydrogenation over Pd/C), PA0 .alpha.-methylbenzyl (deprotect by hydrogenation over Pd/C), or PA0 diphenylmethyl (deprotect by hydrogenation over Pd/C). PA0 Epichlorohydrin, PA0 1-chloro-2,3-epoxy-2-methylpropane, PA0 1-chloro-2,3-epoxybutane, and PA0 3-chloro-1,2-epoxybutane
Japanese Patent No. 32766 (1985) discloses reductive cyclization of 2-cyanoethylglycine ethyl ester using palladium on carbon catalyst and hydrogen at 50.degree. C. and 10 kg/cm.sup.2 pressure for 3 hr. In contrast, in the present invention a different class of reactant and product are involved, the end product being a 3-pyrrolidinol and in further contrast, hydrogenation over palladium on carbon catalyst alone did not produce the cyclization brought about by Raney nickel catalyst in the present invention.
One chemical intermediate useful in the process of the present invention; namely, 4-amino-3-hydroxybutyronitrile is a known compound as reported by Jung, M. E. in J. AMER. CHEM. SOC. 102, 6304 (1980). The carbonate of this compound has been used as an intermediate for the manufacture of .alpha.-amino-.beta.-hydroxybutyric acid as disclosed in JAP. 16,504(66) (C.A. 66, 18309v). 4-Azido-3-hydroxybutyronitrile also useful in the process is known.
British Patent No. 913,856 (C.A. 59, 1787) describes the preparation of 4-(N-methyl-N-phenylamino)-3-hydroxybutyronitrile from 4-(N-methyl-N-phenyl)-3-hydroxybutyl chloride and sodium cyanide in ethanol. The compound is useful in dye preparation. The foregoing anilino derivative is not useful in the process of the present invention as it cannot be reductively cyclized in the process, nor can the phenol radical be removed as can the benzyl radical.
The use of N,N-diethylamino-3-hydroxybutyronitrile in the preparation of high molecular weight therapeutic agents has been described in IOWA STATE COLL. J. SCI. 21, 41-45 (1946) (C.A. 41, 3044b). The compound is not useful in the process of the present invention as it cannot be cyclized thereby.
Compounds prepared by the process of the present invention are useful in the preparation of pharmaceuticals as described in the following U.S. Pat. Nos.:
U.S. Pat. No. 2,838,521 PA1 U.S. Pat. No. 2,830,997 PA1 U.S. Pat. No. 2,956,062 PA1 U.S. Pat. No. 3,301,869 PA1 U.S. Pat. No. 2,882,276 and PA1 U.S. Pat. No. 4,592,866 PA1 hydrogen, PA1 loweralkyl (1-8 C), PA1 loweralkyl (2-8 C), PA1 cycloalkyl (3-9 C), PA1 cycloalkyl-loweralkyl (4-13 C), PA1 phenyl-loweralkyl (7-14 C), and PA1 (Y).sub.1-3 -substituted-phenyl-loweralkyl (7-14 C), PA1 benzyl, PA1 diphenylmethyl, PA1 .alpha.-methylbenzyl, PA1 benzyloxycarbonyl, PA1 diphenylmethoxycarbonyl, PA1 .beta., .beta., .beta.-trichloroethoxycarbonyl, PA1 t-butyloxycarbonyl, or PA1 isobutoxycarbonyl, PA1 loweralkenyl (2-8 C), PA1 cycloalkyl (3-9 C), PA1 cycloalkyl-loweralkyl (4-13 C), PA1 phenyl-loweralkyl (7-14 C), PA1 (Y).sub.1-3 -substituted-phenyl-loweralkyl (7-14 C), PA1 benzyl, PA1 diphenylmethyl, PA1 .alpha.-methylbenzyl, PA1 benzyloxycarbonyl, PA1 diphenylmethoxycarbonyl, PA1 .beta., .beta., .beta.-trichloroethoxycarbonyl, PA1 t-butyloxycarbonyl, or PA1 isobutoxycarbonyl, PA1 (a) a solution having dissolved therein a pyrrolidinol compound having the formula ##STR11## wherein R, R.sup.1, R.sup.2, and R.sup.3 are as defined above, and (b) the catalyst in suspension and separating the catalyst from the slurry to give said pyrrolidinol compound in acid containing solution, PA1 (a) evaporating off the reaction solvent, PA1 (b) adding high boiling diluent and base, to neutralize the acid, giving the free base of the 3-pyrrolidinol, and, PA1 (c) vacuum distilling the free base of said pyrrolidinol compound.